Sex-Dependent Cerebellar Connectivity in Autism Spectrum Disorders

Background: Human neuroimaging studies have documented sex-specific differences in the development, structure, and function of the cerebellum (Nguon et al., 2005). This part of the brain, in conjunction with the cortex, is involved in both sensorimotor and socio-affective processes. These two domains of function are both impaired in autism spectrum disorders (ASD), and not surprisingly, the cerebellum has been highlighted in neuroimaging studies of males with ASD. Behavioral studies have also found sex differences in ASD prevalence and phenotype.

Objectives: Given what we know about the relationship between ASD and the cerebellum, and the sex differences associated with each, we were interested in whether there may be sex-dependent changes in the cerebellum’s functional architecture in ASD. The aim of the current study was to explore this using resting-state functional magnetic resonance imaging (fMRI).

Methods: We collected resting-state fMRI scans from 47 women (23 ASD, and 24 controls) and 120 men (56 ASD, and 64 controls), matched on age, head motion and IQ. Using a measure of global functional connectivity, we ran a linear mixed effects analysis across both groups to determine whether there was a sex-by-diagnosis interaction associated with resting state functional connectivity.

Results: Two clusters in the left and right cerebellum exhibited a diagnosis-by-sex interaction in global connectivity (p< 0.005 with small volume correction in the cerebellum). Compared to controls, females with ASD showed hyperconnectivity between those cerebellar clusters and the cortex, whereas males with ASD showed the opposite pattern (hypoconnectivity with the rest of the brain). Follow-up analyses of seed-based connectivity effects underlying these global connectivity differences (using a 6mm spherical region of interest centered on the peak voxel in each cerebellar cluster) revealed significant diagnosis-by-sex interactions between the cerebellum and several cortical regions including the right fusiform, right inferior frontal gyrus, right precentral gyrus, mid-cingulate, precuneus, middle temporal gyrus, and thalamus.

Conclusions: These results shed light on the sex-specific pathophysiology of ASD. This pattern of sex-dependent, aberrant cerebellar connectivity in ASD might explain some of the abnormalities in motor and socio-affective abilities seen in this population.